The present invention relates to a novel method of preparing ethereally substituted monosaccharides from selectively derivatized monosaccharides. In a further variant, the invention is concerned with an improved method of partially or fully hydrolyzing the resultant ethereally substituted monosaccharide derivatives.
Copending U.S. applications Ser. Nos. 337,134 and 424,786 disclose and claim certain ethereal monosubstitutions of monosaccharides and monosaccharide derivatives. These compounds provide important biological signals which allow living cells to resist virus infections. The compounds are also useful in controlling other types of cell chemistry such as that involved in the formation of memory.
The aforementioned compounds cannot be conveniently synthesized in acceptable yield and in sufficiently high purity for pharmaceutical applications by the most widely accepted method for the synthesis of ethers, i.e., Williamson's synthesis. For instance, the Williamson synthesis has severe disadvantages in the preparation of 3-O- ethers of blocked monosaccharides such as 1,2:5,6-di-O-isopropylidene-D-glucose due in part to the stereochemical problems which are encountered. The only secondary hydroxyl group available in 1,2:5,6-di-O-isopropylidene-D-glucose is too sterically hindered to react at a practical rate with sodium metal to form the sodium salt. Additionally, the resultant sodium salt is almost insoluble in the solvents commonly used in the Williamson synthesis such as ethyl ether or benzene. The handling and preparation of the sodium metal required for synthesizing substantial quantities of 3-O- ethers of blocked monosaccharides and disposing of the excess sodium upon completing the reaction also constitute significant physical hazards.
The second stage of Williamson synthesis, which involves condensation of an alkyl halide with the sodium salt, is efficient and high yields are obtained. However, other problems arise when preparing the alkylamino ethers of monosaccharides. The alkylamino halide which is used in the condensation step must be in the form of the free amine and not as the corresponding mineral acid salt. Many of the amonoalkyl halides are volatile and very toxic when in the form of the free amine, but are not when present in the form of a mineral acid salt. An entirely satisfactory method of synthesizing 3-O- ethers of monosaccharides must therefore be capable of employing the aminoalkyl halide in the form of the mineral acid salt to avoid the inherent disadvantages of volatility and toxicity.
Still another method of condensing organic halides with blocked monosaccharides is disclosed in U.S. Pat. No. 2,715,121. This method involves autoclaving of the reaction mixture at high temperature under steam pressure and, when employed for the preparation of alkylamino ethers of monosaccharides, low yields of impure reaction products are obtained due to the preponderance of side reactions and the synthesis of side products. It is also very difficult to separate a desired substantially pure ether of monosaccharides from the reaction mixture which is sufficiently free of impurities for use in the therapeutic treatment treatment of warm-blooded animals.
In view of the foregoing, it is apparent that the art has long sought an entirely satisfactory method of preparing ethers of monosaccharides in high yield and purity which does not require hazardous chemicals or vigorous reaction conditions. However, such a method was not available prior to the present invention.
It is an object of the present invention to provide a novel method of preparing ethers of monosaccharides in high yield and purity.
It is a further object to provide a novel method of preparing ethers of monosaccharides wherein side reactions and side products are almost absent, and which requires mild reaction conditions and relatively nontoxic and nonhazardous reactants.
Still other objects and advantages of the invention will be apparent to those skilled in the art upon reference to the following detailed description and the examples.